Therapeutically useful 3,4,5-trimethoxybenzene derivatives

ABSTRACT

Compounds of the formula I ##STR1## wherein m and n are 0, 1 or 2, X represents oxygen, imino, benzylimino, or morpholinoethylimino, Y represents CO, CONH, COO or SO 2 , and NR 1  R 2  represents a dimethylamino, diethylamino, dipropylamino, dibutylamino, allylamino, isobutenylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, cyclooctylamino, N-methyl N-cyclopentylamino, N-methyl N-cyclohexylamino, N-allyl N-cyclohexylamino, adamantylamino, diethoxyethylamino, dimethylaminoethylamino, dimethylaminopropylamino, N-methyl N-dimethylaminopropyl-amino, benzylamino, 3,4,5-trimethoxybenzylamino, phenethylamino, p-chlorophenethylamino, tetrahydrofurfurylamino, tetrahydropyranylmethylamino, pyrrolidino, isoxazolidinyl, piperidino, 4-hydroxypiperidino, 4-m-chlorophenyl-4-hydroxypiperidino, homopiperidino, 1,2,3,6-tetrahydropyridyl, morpholino, 2-methylmorpholino, 2,6-dimethylmorpholino, 2-morpholinoethylamino, thiamorpholino, piperazino, 4-methylpiperazino, 4-(α-m-chlorophenyl-benzyl)-piperazino, 4-(3,4,5-trimethoxyphenylaminocarbonyl)-piperazino, 4-(3,4,5-trimethoxyphenylaminocarbonylmethyl)-piperazino, 4-phenylpiperazino, 4-m-trifluoromethylphenyl-piperazino, 4-piperidinocarbonylmethyl-piperazino, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, (7-chloro-4-quinolyl)-amino, 1,2,3,4-tetrahydrobenzoxazinyl or 1,2,3,4-tetrahydro-6-chlorobenzoxazinyl group, and their pharmaceutically acceptable acid addition salts are novel and are therapeutically useful, in particular as tranquillizers, myorelaxants and anticonvulsants.

The present invention relates to derivatives of 3,4,5-trimethoxybenzene, their preparation as well as their therapeutical use, in particular as tranquillisers, myorelaxants and anticonvulsants.

According to the present invention there are provided compounds of the formula I ##STR2## wherein each of m and n, which may be the same or different, represents 0, 1 or 2,

X represents an oxygen atom or an imino group of formula NR₃ (wherein R₃ represents a hydrogen atom or a benzyl or morpholinoethyl group),

Y represents one of the divalent groups CO, CONH, COO or SO₂, and

NR₁ R₂ represents a dimethylamino, diethylamino, dipropylamino, dibutylamino, allylamino, isobutenylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, cyclooctylamino, N-methyl N-cyclopentylamino, N-methyl N-cyclohexylamino, N-allyl N-cyclohexylamino, adamantylamino, diethoxyethylamino, dimethylaminoethylamino, dimethylaminopropylamino, N-methyl N-dimethylaminopropyl-amino, benzylamino, 3,4,5-trimethoxybenzylamino, phenethylamino, p-chlorophenethylamino, tetrahydrofurfurylamino, tetrahydropyranylmethylamino, pyrrolidino, isoxazolidinyl, piperidino, 4-hydroxypiperidino, 4-p-chlorophenyl-4-hydroxypiperidino, homopiperidino, 1,2,3,6-tetrahydropyridyl, morpholino, 2-methylmorpholino, 2,6-dimethylmorpholino, 2-morpholinoethylamino, thiamorpholino, piperazino, 4-methylpiperazino, 4-(α-m-chlorophenyl-benzyl)-piperazino, 4-(3,4,5-trimethoxyphenylaminocarbonyl)-piperazino, 4-(3,4,5-trimethoxyphenylaminocarbonylmethyl)-piperazino, 4-phenylpiperazino, 4-m-trifluoromethylphenyl-piperazino, 4-piperidinocarbonylmethyl-piperazino, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, (7-chloro-4-quinolyl)-amino, 1,2,3,4-tetrahydrobenzoxazinyl or 1,2,3,4-tetrahydro-6-chlorobenzoxazinyl group,

as well as their pharmaceutically acceptable acid addition salts.

Preferred compounds of the invention are those of the formula ##STR3## (wherein X and NR₁ R₂ are as defined above) and their pharmaceutically acceptable acid addition salts; those of the formula ##STR4## (wherein X, m and NR₁ R₂ are as defined above) and their pharmaceutically acceptable acid addition salts; and those of the formula ##STR5## (wherein Y, n and NR₁ R₂ are as defined above) and their pharmaceutically acceptable acid addition salts.

Preferably NR₁ R₂ represents a dimethylamino, morpholino, 2,6-dimethylmorpholino, piperidino or 4-methylpiperazino group, especially a morpholino group.

The compounds of the formula I according to the present invention may be obtained from known compounds according to the following general scheme: ##STR6##

In these formulae A represents a --N═C═O, NH₂, OH or --NH--(CH₂)_(m) --CO--hal group, B represents H, NH₂, OH, hal--CO-- or hal--SO₂ --, hal being a halogen, preferably chlorine, atom, and

NR₁ R₂, m and n have the same meanings as in formula I.

Compounds of the formula I wherein X represents a group of formula NR₃ wherein R₃ is other than hydrogen may be prepared from the corresponding compound where R₃ is hydrogen.

Pharmaceutically acceptable acid addition salts may be prepared in conventional manner by reaction of a base of the formula I with a pharmaceutically acceptable acid.

The various usable reactants are illustrated in the general preparations given below. The symbols NR₁ R₂ and hal the same meanings as above.

(A) UREAS

When m=n=0; X=NH; Y=CO, the corresponding ureas may be prepared either by reaction of an isocyanate with an amine according to the scheme: ##STR7## or by reaction of an aniline with an N-chloroformylated amine according to the scheme: ##STR8##

(B) O-ARYLCARBAMATES

When m=n=0; X=O; Y=CO, the corresponding carbamates may be prepared by reaction of a phenol (which may be in the form of a salt e.g. sodium salt) with an N-chloroformylated amine according to the scheme: ##STR9##

(C) SEMI CARBAZIDES

When m=n=0; X=NH; Y=CO--NH, the corresponding semi-carbazides may be prepared by reaction of an isocyanate with a hydrazine according to the scheme: ##STR10##

(D) N-ARYL CARBAMATES

When m=n=0; X=NH; Y=COO, the corresponding carbamates may be prepared by reaction of an isocyanate with a hydroxylamine according to the scheme: ##STR11##

When m=0; n=1 or 2; X=NH; Y=COO, the corresponding carbamates may be prepared by reaction of an isocyanate with an alcohol according to the scheme: ##STR12##

(E) SULPHAMIDES

When m=n=0; X=NH; Y=SO₂, the corresponding sulphamides may be prepared by reaction of an aniline with an N-chlorosulphonated amine according to the scheme: ##STR13##

(F) 2-ANILINO-ACETAMIDES AND 3-ANILINO-PROPIONAMIDES

When m=1 or 2; n=0; X=NH; Y=CO, the corresponding amides may be prepared by reaction of an acid halide with an amine according to the scheme: ##STR14##

(G) N-ARYL-ACETAMIDES AND PROPIONAMIDES

When m=0; n=1 or 2; X=NH; Y=CO, the corresponding amides may be prepared by reaction of an aniline with an acid halide according to the scheme: ##STR15##

The invention also provides a pharmaceutical composition which contains a compound of the formula I or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable carrier or diluent.

The invention further provides a method of treating a human patient which method comprises administering to the patient a compound of the formula I or a pharmaceutically acceptable acid addition salt thereof.

The following non-limiting Examples illustrate the invention.

EXAMPLE 1 2,6-Dimethyl-4-[N-(3,4,5-trimethoxyphenyl)-carbamoyl]-morpholine. (C₁₆ H₂₄ N₂ O₅ =324.38)

To a stirred solution of 4.0 g (0.019 mole) 3,4,5-trimethoxyphenyl-isocyanate in 100 ml anhydrous ether are added 2.4 g (0.021 mole) 2,6-dimethylmorpholine. The mixture is heated at the reflux temperature of the solvent, with stirring, for 7 hours.

After cooling, the precipitate is dried, washed with ether and dried. The colourless liquid thus obtained (4.9 g; 79% yield) is recrystallised from water to give the pure product which melts at 117°-118° C.

EXAMPLE 2 1-Methyl-4-[N-(3,4,5-trimethoxyphenyl)-carbamoyl]piperazine (hydrochloride)

A solution of 10 g (0.061 mole) 1-methyl-4-chloroformyl-piperazine in 100 ml dry methylene chloride is added to a solution of 11.2 g (0.061 mole) 3,4,5-trimethoxy-aniline in a 100 ml methylenechloride. After stirring at ambient temperature for 24 hours, the solvent is evaporated off in vacuo; the residue is dissolved in the minimum of ethanol and then the crude hydrochloride precipated by the addition of diethyl ether, and dried.

Purification by recrystallisation from an acetone 3-ethanol 1 mixture gives the pure product (9.4 g; 44% yield) which melts at 184°-86° C.

EXAMPLE 3 4-(3,4,5-Trimethoxyphenoxycarbonyl)-morpholine (C₁₄ H₁₉ NO₆ =297.31)

To a solution of 10.15 g (0.049 mole) sodium 3,4,5-trimethoxyphenolate in 100 ml anhydrous dimethylformamide are added gradually, with stirring, 7.5 g (0.050 mole) N-chloroformyl-morpholine.

The reaction is clearly exothermic. After the completion of the addition, the mixture is heated at about 50° C. for 2 hours. The sodium chloride is then separated off by filtration and the solvent evaporated off in vacuo.

The solid obtained by washing of the crude product with water is recrystallised from ethanol to give 9.6 g pure product (65% yield) melting at 118°-119° C.

EXAMPLE 4 N-(3,4,5-trimethoxyphenyl) N'-morpholino-urea. (C₁₄ H₂₁ N₃ O₅ =311.34)

A solution of 2.6 g (0.025 mole) 4-aminomorpholine in 50 ml anhydrous ether is added, with stirring, to a solution of 5.0 g (0.024 mole) 3,4,5-trimethoxyphenyl-isocyanate in 200 ml dry ether.

The solution is then heated at the reflux of the solvent, with stirring, for 4 hours 30 minutes. After cooling, the precipitate is dried and washed with ether. The colourless solid obtained (7.0 g: 94% yield) is purified by recrystallisation from water. Melting point=204° C.

EXAMPLE 5 N-(2-morpholino-ethoxycarbonyl)-3,4,5-trimethoxyaniline. (C₁₆ H₂₄ N₂ O₆ =340.38)

A solution of 5.0 g (0.024 mole) 3,4,5-trimethoxyphenyl-isocyanate and 3.4 g (0.026 mole) 4-(2-hydroxyethyl)-morpholine in 300 ml anhydrous ether is heated under reflux, with stirring, for 7 hours.

The solvent is evaporated off under vacuum and then the oily residue is triturated in isopropyl ether.

The crystals obtained are dried to give 5.5 g (67% yield) of a colourless solid. Purification is readily effected by silica chromatography (Merck 7754) using ethyl acetate as eluant.

Melting point=81°-82° C.

EXAMPLE 6 4-[N-(3,4,5-trimethoxyphenyl)-sulphamoyl]-morpholine. (C₁₃ H₂₀ N₂ O₆ S=332.38)

To a solution of 4.8 g (0.026 mole) 3,4,5-trimethoxyaniline and 2.6 g (0.026 mole) triethylamine in 200 ml dry benzene are added 5.7 g (0.031 mole) N-chlorosulphonyl morpholine.

The mixture obtained is heated at the reflux of the solvent, with stirring, for 14 hours. After evaporation of the solvent under vacuum, the oily residue is taken up in a mixture of water and ethyl acetate. The two phases are decanted, the organic phase washed with a 2 N-hydrochloric acid solution, dried and concentrated to dryness; the residual solid is triturated in ether and the insoluble material dried to give 4.1 g of a slightly coloured solid (47% yield). Purification is by recrystallisation from water.

Melting point=148° C.

EXAMPLE 7 4-[2-(3,4,5-trimethoxyanilino)-acetyl]-morpholine. (C₁₅ H₂₂ N₂ O₅ =310.35)

A mixture of 12.8 g (0.07 mole) 3,4,5-trimethoxyaniline, 12.6 g (0.077 mole) N-chloroacetyl-morpholine and 7.8 g (0.077 mole) triethylamine in 300 ml anhydrous benzene is heated at the reflux of the solvent, with stirring, for 14 hours.

After cooling, the triethylamine hydrochloride is separated off by filtration and then the organic phase is concentrated under vacuum.

The residual oil obtained, triturated in diethyl ether, gives on agglomeration a solid which is dried and washed with ether several times to give, after drying, 19.3 g of a slightly coloured solid (89% yield).

Purification is by silica chromatography (Merck 7754) with elution with ethyl acetate and recrystallisation from ethanol.

Melting point=136° C.

EXAMPLE 8 2-Morpholino-N-(3,4,5-trimethoxyphenyl)-acetamide

To a solution of 1.3 g (0.15 mole) morpholine and 1.6 g (0.016 mole) triethylamine in 75 ml dry benzene are added, in fractions with stirring and slight cooling, 4.3 g (0.016 mole) 2-chloro-N-(3,4,5-trimethoxyphenyl)acetamide.

After completion of the addition, the mixture is heated at the reflux of the solvent for 20 hours. After cooling, the triethylamine hydrochloride formed is dried and washed with benzene.

The organic phase is concentrated under vacuum, the residual paste obtained is recrystallised from ethanol to give 2.6 g of a slightly coloured solid (56% yield) melting at 110°-111° C.

EXAMPLE 9 N-morpholinocarbonyl, N-(2-morpholinoethyl)-3,4,5-trimethoxyaniline hydrochloride. (C₂₀ H₃₁ N₃ O₆. HCl=445.95)

Under an inert atmosphere 0.45 g sodium hydride is added to a solution of 5 g (0.017 mole) N-(morpholino-carbonyl)-3,4,5-trimethoxyaniline, prepared according to Example 1 or 2, in 30 ml dry dimethyl formamide. After stirring at ambient temperature until the evolution of hydrogen ceases, there are added 0.5 g sodium hydride and then, by fractions, 4.1 g (0.022 mole) 4-(2-chloroethyl)morpholine hydrochloride.

The mixture is stirred and heated to 85° C. for 10 hours.

After filtration and evaporation of solvent under vacuum, the residue is taken up in water. The aqueous phase is acidified with an N-hydrochloric acid solution, extracted with chloroform, made alkaline with sodium bicarbonate solution and extracted several times with chloroform. The organic phase is dried over sodium sulphate and concentrated under vacuum, giving 6.4 g of oily residue (93% yield).

This, dissolved in ether, is added to the necessary quantity of hydrochloric ether; the precipitate, dried, washed with dry ether and recrystallised from isopropanol, gives the pure hydrochloride:

Melting point (Tottoli)=204°-206° C.

The following Tables I, II and III contain the compounds of the preceding Examples 1 to 9 as well as other compounds prepared in an analogous manner.

                                      TABLE I                                      __________________________________________________________________________      ##STR16##                                                                                                          Accord-  Melting                                                                               Elementary                                                     ing to                                                                              Yield                                                                              Point  Analysis (%)              No LJ                                                                              X           NR.sub.1 R.sub.2     Example                                                                             (%) (°C.)                                                                          Calculated                                                                           Found               __________________________________________________________________________     800 NH                                                                                          ##STR17##           1    83  176-77                                                                              C H N                                                                            61.21 7.53 9.51                                                                      61.23 7.76                                                                     9.63                801 NH                                                                                          ##STR18##           1    89  151-52                                                                              C H N                                                                            62.31 7.84 9.08                                                                      62.03 7.86                                                                     9.02                778 NH                                                                                          ##STR19##           1    93  188  C H N                                                                            62.31 7.84 9.08                                                                      62.18 7.82                                                                     8.95                802 NH                                                                                          ##STR20##           1    84  197-98                                                                              C H N                                                                            63.33 8.12 8.64                                                                      63.52 3.20                                                                     3.59                811 NH                                                                                          ##STR21##           1    84  148  C H N                                                                            65.49 8.10 8.04                                                                      65.40 8.13                                                                     8.14                799 NH                                                                                          ##STR22##           1    84  202-204                                                                             C H N                                                                            63.33 8.12 8.68                                                                      63.43 8.22                                                                     8.60                781 NH                                                                                          ##STR23##           1    91  214-15                                                                              C H N                                                                            64.26 8.38 8.32                                                                      64.44 8.56                                                                     8.08                813 NH                                                                                          ##STR24##           1    87  144-45                                                                              C H N                                                                            62.32 7.84 9.08                                                                      62.37 7.94                                                                     8.99                820 NH                                                                                          ##STR25##           1    74  150-51                                                                              C H N                                                                            55.31 6.43 9.92                                                                      55.41 6.49                                                                     9.88                733 NH                                                                                          ##STR26##           1 and 2                                                                             92  154-55                                                                              C H N                                                                            56.74 6.80 9.45                                                                      56.73 6.91                                                                     9.49                754 O                                                                                           ##STR27##           3    65  118-19                                                                              C H N                                                                            56.56 6.44 4.71                                                                      56.74 6.51                                                                     4.83                799 NH                                                                                          ##STR28##           1    83  240-42                                                                              C H N                                                                            66.64 7.83 7.77                                                                      66.50 7.94                                                                     7.58                775 NH                                                                                          ##STR29##           1    68  144-45                                                                              C H N                                                                            56.68 56.88  7.18                                                                    11.05               809 NH                                                                                          ##STR30##           1    89  132  C H N                                                                            59.56 7.85 9.92                                                                      59.54  7.99                                                                    10.11               812 NH                                                                                          ##STR31##           1    82  126-27                                                                              C H N                                                                            59.99 7.19  9.99                                                                     59.99 7.35                                                                     9.87                780 NH                                                                                          ##STR32##           1    78  126-27                                                                              C H N                                                                            63.87 8.93 8.27                                                                      64.00 8.94                                                                     8.23                810 NH                                                                                          ##STR33##           1    90  173-74                                                                              C H N                                                                            59.99 7.19 9.99                                                                      60.14  7.36                                                                    10.17               776 NH                                                                                          ##STR34##           1    86  142-43                                                                              C H N                                                                            61.20 7.53 9.52                                                                      61.59 7.50                                                                     9.58                814 NH                                                                                          ##STR35##           1    95  174-75                                                                              C H N                                                                            58.05 7.14 9.02                                                                      58.19 7.13                                                                     9.16                819 NH                                                                                          ##STR36##           1    94  159-60                                                                              C H N                                                                            61.63 6.89 9.58                                                                      61.77 6.93                                                                     9.47                879 NH                                                                                          ##STR37##           1    92  164-65                                                                              C H N                                                                            66.65 6.48 8.18                                                                      66.65 6.56                                                                     8.15                880 NH                                                                                          ##STR38##           1    90  135  C H N                                                                            66.65 6.48 8.18                                                                      66.58 6.64                                                                     8.07                816 NH                                                                                          ##STR39##           1    63  138-39                                                                              C H N                                                                            58.05 7.15 9.03                                                                      58.21 7.25                                                                     9.05                788 NH                                                                                          ##STR40##           1    77  117-18                                                                              C H N                                                                            59.24 7.45 8.63                                                                      59.19 7.49                                                                     8.51                804 NH                                                                                          ##STR41##           1    84  144-45                                                                              C H N S                                                                          53.83  6.45  8.97                                                              10.26 53.84  6.49                                                                    8.93 10.35          759 NH                                                                                          ##STR42##           2    44  184-86                                                                              C H N                                                                            52.09 51.91  7.12                                                                    11.89               767 O                                                                                           ##STR43##           3    66  244  C H N                                                                            51.94 6.68 8.08                                                                      52.44 6.79                                                                     8.19                795 NH                                                                                          ##STR44##           1    72  196-97                                                                              C H N                                                                            65.38 6.09 8.47                                                                      65.39 6.12                                                                     8.44                840 NH                                                                                          ##STR45##           1    56  >250 C H N                                                                            56.13  6.59 10.90                                                              hemi- hydrate                                                                        56.12  6.32                                                                    11.03               774 NH                                                                                          ##STR46##           1    96  156  C H N                                                                            62.78 5.85 8.13                                                                      62.84 5.87                                                                     8.10                773 O                                                                                           ##STR47##           3    45  176  C H N                                                                            62.60 62.78  5.59                                                                    4.06                770 NH                                                                                          ##STR48##           1    78  166-67                                                                              C H N                                                                            57.07 57.17  5.21                                                                    7.27                798 NH                                                                                          ##STR49##           1    90  140-42                                                                              C H N                                                                            59.10 59.19  6.53                                                                    6.80                783 NH                                                                                          ##STR50##           1    70  144-45                                                                              C H  N                                                                           65.43 65.37  6.64                                                                    8.46                796 NH                                                                                          ##STR51##           1    85  178-80                                                                              C H N                                                                            59.26 59.24  5.81                                                                    7.61                797 NH                                                                                          ##STR52##           1    74  113-14                                                                              C H N                                                                            58.05 58.24  7.23                                                                    8.91                815 NH                                                                                          ##STR53##           1    86  129-30                                                                              C H N                                                                            59.24 59.07  7.24                                                                    8.66                877 NH                                                                                          ##STR54##           1    61  97-98                                                                               C H N                                                                            56.13 55.98  7.77                                                                    8.04                784 NH                                                                                          ##STR55##           1    78  117-18                                                                              C H N                                                                            57.86 57.98  8.22                                                                    13.53                   NH                                                                                          ##STR56##           1    94  144-45 (HCl)                                                                        C H N                                                                            56.62 56.58  7.65                                                                    12.20               785 NH                                                                                          ##STR57##           1    80  86-87                                                                               C H N                                                                            57.86 57.83  8.23                                                                    13.29               805 NH                                                                                          ##STR58##           1    63  81-83                                                                               C H N                                                                            59.05 59.19  8.38                                                                    12.97               777 NH                                                                                          ##STR59##           1    68  228-230                                                                             C H N                                                                            58.84 58.70  4.66                                                                    10.73               830 (HCl)                                                                          NH                                                                                          ##STR60##           1    62  150  C H N                                                                            59.98 60.16  7.70                                                                    13.27               821                                                                                 ##STR61##                                                                                  ##STR62##           9    78  101-103                                                                             C H N                                                                            65.27 65.16  6.63                                                                    7.27                822                                                                                 ##STR63##                                                                                  ##STR64##           9    93  204-206                                                                             C H N                                                                            53.87 53.56 7.16                                                                     9.54                    (hydro-                                                                        chloride)                                                                  __________________________________________________________________________

                                      TABLE II                                     __________________________________________________________________________      ##STR65##                                                                                             Accord-  Melting                                                               ing to                                                                              Yield                                                                              Point                                                                               Elementary Analysis (%)                  No LJ Y  NR.sub.1 R.sub.2                                                                            m Example                                                                             (%) (°C.)                                                                           Calculated                                                                           Found                           __________________________________________________________________________     793   CO                                                                                 ##STR66##   1 7    89  136  C H N                                                                             58.05 7.14 9.03                                                                      58.00 7.17 8.98                 837   CO                                                                                 ##STR67##   1 7    51  147  C H N                                                                             65.43 65.42  7.18 11.21               786   CO                                                                                 ##STR68##   1 7    47  156-158                                                                             C H N                                                                             59.43 59.31  7.82 13.05               782 (HCl:839)                                                                        CO                                                                                 ##STR69##   1 7    41  129  C H N                                                                             63.67 6.13 7.81                                                                      63.75 6.13 7.73                 762   CO                                                                                 ##STR70##   1 7    52  178  C H N                                                                             58.09 5.39 7.13                                                                      58.18 5.40 7.03                 __________________________________________________________________________

                                      TABLE III                                    __________________________________________________________________________      ##STR71##                                                                                                         Accord-  Melting                                                               ing to                                                                              Yield                                                                              Point                                                                               Elementary Analysis                                                            (%)                          No LJ Y      NR.sub.1 R.sub.2     n Example                                                                             (%) (°C.)                                                                           Calculated                                                                           Found               __________________________________________________________________________     807                                                                                   ##STR72##                                                                             ##STR73##           0 4    94  204  C H N                                                                             54.01 53.97  6.82                                                                    13.55               828                                                                                   ##STR74##                                                                             ##STR75##           0 4    82  160-61                                                                              C H N                                                                             53.84 53.65  6.36                                                                    9.03                787 phosphate  833                                                                   CO                                                                                     ##STR76##           1 8    56  110-11                                                                              C H N                                                                             58.05 57.96  7.22                                                                    8.90                817   CO                                                                                     ##STR77##           2 8    81  113-14                                                                              C H N                                                                             59.24 59.16  7.51                                                                    8.70                792   CO                                                                                     ##STR78##           1 8    43  159  C H N                                                                             63.67 63.58  6.16                                                                    7.79                818                                                                                   ##STR79##                                                                             ##STR80##           2 5    67  81-82                                                                               C H N                                                                             56.46 56.43  7.08                                                                    8.16                791   SO.sub.2                                                                               ##STR81##           0 6    47  148  C H N                                                                             46.98 47.03  6.16                                                                    8.42                881   CO                                                                                     ##STR82##           1 8    42  81-82                                                                               C H N                                                                             62.32 62.45  7.88                                                                    9.08                829   CO                                                                                     ##STR83##           2 8    68  227 (hydro- chloride)                                                               C H N                                                                             52.9753.10  6.576.28                                                            6.575.39 (hydrochlor                                                          ide dihydrate)            838 (HCl)                                                                            CO                                                                                     ##STR84##           1 8    70  240 (hydro- chloride)                                                               C H N                                                                             58.2758.07  5.785.85                                                            9.279.12                 841   CO                                                                                     ##STR85##           2 8    72  238-40 (hydro- chloride)                                                            C H N                                                                             54.8154.66  5.805.91                                                            8.348.23 (hydrochlor                                                          ide)                      848   CO                                                                                     ##STR86##           1 8    85  228-30 (dihydro- chloride)                                                          C H N                                                                             51.5751.26  6.326.47                                                            9.259.23  (dihydroch                                                          loride)                   834   CONHCO                                                                                 ##STR87##           1 7    92  136-38 HCl 212-214                                                                  C H N                                                                             54.39 54.35   6.56                                                                   11.47               __________________________________________________________________________

The compounds of the invention have been subjected to pharmacological tests. Acute toxicity of different compounds has been determined and their activity in the region of the central nervous system has been tested.

1--ACUTE TOXICITY FOR ORAL ADMINISTRATION IN MICE

The compounds are administered orally in increasing doses in suspension in a 10% gum arabic solution to groups of 5 ♀ mice of mean weight 25 g. The 50% lethal doses (LD 50) are calculated by the method of KARBER and BEHRENS (Arch. Exp. Path. Pharmakol. 1935, 177, 379-388).

The LD 50's found are summarised in Table IV below and indicate that the tested compounds have low toxicity.

2--ACTIVITY IN THE REGION OF THE CENTRAL NERVOUS SYSTEM 2.1--Action on spontaneous motor activity in the mouse

This test has been carried out according to the method of BOISSIER (Arch. Int. Pharmacodyn. 1945, 158, 212). 30 minutes after administration per os of the test compounds, the mice (groups of 12 animals) are installed in individual cages in a BOISSIER activity measuring cupboard and move about before two photoelectric cells placed according to the rectangular coordinates. Meters register the movement during 20 minutes. The mean number of movements are calculated for the control group and the treated groups and the variations in motor activity of the treated groups are expressed as percentages based on the results for the control group.

Table V below shows that the test compounds reduce spontaneous motor activity in the mouse.

2.2--Action on the pentobarbital hypnosis time in the mouse

30 minutes after administration per os of the compounds, the mice (groups of 10 animals) receive an injection of pentobarbital at a dose (50 mg/kg i.v.) which dose causes the control animals, which have received only administration vehicle (i.e. 10% gum arabic solution), to sleep for about 30 to 60 minutes. The hypnosis time of each mouse is counted in minutes from the moment when the animal may be placed without resistance on its back until that when it spontaneously gets back on its feet. In the treated groups and the control group, the average hypnosis times are calculated and the results obtained in the treated groups are expressed as percentages of the variation of hypnosis time based on the control group.

The results of Table VI below show that the test compounds increase the narcotic effect of pentobarbital.

2.3--Test on the action against the convulsant effects of electric shock and of strychnine in the mouse

30 minutes after administration of the compounds to groups of 10 animals, there is investigated the protection induced against:

tonic crisis (extension of rear feet) provoked by supramaximal transcranial electric stimulation (13 to 16 mA for 0.1 sec).

convulsive crisis and death provoked by injection of strychnine at a limiting lethal dose of 1.5 mg/kg s.c.

The results are expressed as a percentage of protection based on a control group which have only received the administration vehicle for the compounds.

The results of Tables VII and VIII show that the test compounds at to reduce, in a manner more or less intense, the convulsant effects of strychnine and of electric shock.

                  TABLE IV                                                         ______________________________________                                         ACUTE TOXICITY FOR ALL ADMINISTRATION                                          IN MICE                                                                        Compounds             LD 50 in mg/kg                                           ______________________________________                                         767                   1025                                                     793 - 820             1250                                                     788                   1350                                                     775 - 786             1700                                                     812                   2000                                                     785                   2200                                                     787 - 801 - 805 - 807 -816 - 821                                                                     2500                                                     809 - 813 - 833       3000                                                     784 - 834             3375                                                     818                   3500                                                     776 - 810             3750                                                     733 - 759             4000                                                     797                   4400                                                     754 - 811 - 814 - 815 - 817 - 819 -                                                                  5000                                                     822 - 830                                                                      762 - 770 - 773 - 774 - 777 - 778 -                                            779 - 780 - 781 - 782 - 783 - 791 -                                                                  >5000                                                    792 - 795 - 796 - 798 - 799 - 800 -                                            802 - 804 - 828 - 829 - 837 - 838 -                                            839 - 840 - 841 - 848                                                          ______________________________________                                    

                  TABLE V                                                          ______________________________________                                         ACTION ON SPONTANEOUS MOTOR                                                    ACTIVITY IN THE MOUSE                                                          Compounds  Doses in    Pecentage variation                                     Nos. LJ    mg/kg p.o.  in motor activity (%)                                   ______________________________________                                         733        400         -74                                                     754        500         -41                                                     759        400         -45                                                     775        170         -40                                                     776        375         -48                                                     786        170         -20                                                     787        250         -84                                                     788        135         -34                                                     789        250         -62                                                     790        125         -37                                                     791        500         -53                                                     798        500         -20                                                     801        250         -29                                                     804        500         -24                                                     807        250         -33                                                     809        300         -78                                                     810        375         -38                                                     817        500         -17                                                     818        350         -33                                                     819        500         -18                                                     ______________________________________                                    

                  TABLE VI                                                         ______________________________________                                         ACTION ON THE PENTOBARBITAL                                                    HYPNOSIS TIME IN THE MOUSE                                                                             Percentage variat-                                     Compounds  Doses in     ion in pentobarbitol                                   Nos. LJ    mg/kg p.o.   hypnosis time (%)                                      ______________________________________                                         733        400          +164                                                   754        500          +178                                                   759        400          +22                                                    775        170          +149                                                   776        375          +130                                                   786        170          +172                                                   787        250          +141                                                   790        125          +270                                                   791        500          +200                                                   798        500          +145                                                   801        250          +70                                                    804        500          +120                                                   807        250          +98                                                    809        300          +157                                                   810        375          +148                                                   817        500          +300                                                   818        350          +180                                                   ______________________________________                                    

                  TABLE VII                                                        ______________________________________                                         ACTION AGAINST THE CONVULSANT                                                  EFFECTS OF STRYCHNINE IN THE                                                   MOUSE                                                                                                 Percentage protect-                                                            ion against the con-                                    Compound Nos.                                                                             Doses in    vulsant effects of                                      LJ         mg/kg p.o.  strychnine (%)                                          ______________________________________                                         733        400         100                                                     754        500         100                                                     759        400         55                                                      775        170         33                                                      776        375         44                                                      789        250         78                                                      790        125         78                                                      801        250         100                                                     819        500         70                                                      ______________________________________                                    

                  TABLE VIII                                                       ______________________________________                                         ACTION AGAINST THE CON-                                                        VULSANT EFFECTS OF ELECTRIC                                                    SHOCK IN THE MOUSE                                                                                    Percentage protect-                                                            ion against the con-                                    Compounds Nos.                                                                            Doses in    vulsant effects of                                      LJ         mg/kg p.o.  the electric shock (%)                                  ______________________________________                                         733        400         30                                                      754        500         90                                                      798        500         40                                                      801        250         37                                                      809        300         80                                                      810        375         70                                                      817        500         40                                                      819        500         40                                                      ______________________________________                                    

These results shows that the compounds of the invention possess tranquillising, sedative and myorelaxant effects. They are thus appropriate in the treatment of psychosomatic affections.

The theraputic indications of the compounds of the invention concern:

anxiety, hyperemotivity, neurotic states, character troubles,

functional troubles, neurovegative dystonis,

contractions of muscular origin, lumbagos, torticollis, painful cramps etc.

The compounds of the invention may be administered orally, rectally, parenterally, by aerosol or may be used externally.

For oral administration the mean posology is 1 to 3 g per day for an adult.

Preferred pharmaceutical forms are tablets, capsules, syrups, drinkable suspensions, suppositories, injectable solutions, aerosols, skin creams, liniments etc. 

We claim:
 1. A compound of the formula ##STR88## wherein m is selected from O and the numbers 1 and 2,X is selected from oxygen and an imino group of the formula NR₃,(wherein R₃ is selected from hydrogen benzyl, and morpholinoethyl), Y is selected from the divalent groups CO, CONH, and COO and SO₂, and NR₁ R₂ is selected from the group consisting of morpholino, 2-methylmorpholino, 2,6-dimethylmorpholino, 2-morpholinoethylamino, and thiamorpholino,and their pharmaceutically-acceptable acid addition salts.
 2. A compound according to claim 1 which is of the formula ##STR89## (wherein X and NR₁ R₂ are as defined in claim 1) and its pharmaceutically-acceptable acid addition salts.
 3. A compound according to claim 1 which is of the formula ##STR90## (wherein Y, m and NR₁ R₂ are as defined in claim 1) and its pharmaceutically-acceptable acid addition salts.
 4. A compound according to claim 1 wherein NR₁ R₂ represents a morpholino or 2,6-dimethylmorpholino.
 5. A compound according to claim 1 which is selected from 4-[N-(3,4,5-trimethoxyphenyl)-carbamoyl]-morpholine and 4-(3,4,5-trimethoxyphenoxycarbonyl)-morpholine.
 6. 4-(3,4,5-Trimethoxyphenoxycarbonyl)-morpholine, and its pharmaceutically-acceptable acid addition salts.
 7. 4-[N-(3,4,5-trimethoxyphenyl)-carbamoyl]-morpholine, and its pharmaceutically-acceptable acid addition salts.
 8. A pharmaceutical composition, useful for its tranquilizing, muscle relaxing and sedative effects, which comprises a pharmaceutically effective amount of a compound of claim 1, or a pharmaceutically acceptable acid-addition salt thereof together with a pharmaceutically acceptable carrier or diluent.
 9. A pharmaceutical composition according to claim 7 which contains a compound selected from 4-[N-(3,4,5-trimethoxyphenyl)-carbamoyl]-morpholine and 4-(3,4,5-trimethoxyphenoxycarbonyl)-morpholine.
 10. A method for treating a human patient which comprises administering to said patient for its tranquilizing, muscle relaxing and sedative effects, a therapeutically-effective amount of a compound of claim 1 or a pharmaceutically-acceptable acid-addition-salt thereof.
 11. A method according to claim 10 wherein there is administered a compound selected from 4-[N-(3,4,5-trimethoxyphenyl)-carbamoyl]-morpholine and 4-(3,4,5-trimethoxyphenoxycarbonyl)-morpholine. 